Principal Investigator/Program Director (Last, first, middle): Hedrick, Stephen M. 1 R01 AI073885-01A2 PROJECT SUMMARY/ABSTRACT Hematopoietic cells constantly turn over. Their rates of division and death determine the steady-state number of cells and size of lymphoid organs. In particular, T lymphocytes are held in a state of active quiescence that can be relieved to allow for dramatic expansions and contractions associated with infection. Whether there is a connection between active quiescence, homeostasis, regulation of antigen-mediated expansion and tolerance is presently lmknown. The hypothesis to be tested in this proposal is that some or all of these aspects of T cell physiology are importantly regulated by a family of transcription factors known to integrate multiple inputs: growth factors, nutrients, and stress. This family has been termed FOXO for Forkhead bOX with the second 0 denoting one of 19 subfamilies consisting of five members related by sequence. We find that Foxo1 and Foxo3 mediate important regulatory functions in T cells and dendritic cells, respectively. The experiments described in this application are designed to lmderstand the mechanisms lmderlying this regulation, and determine how Foxo factors regulate lymphoproliferation, survival, autoimmune disease, and self-tolerance.